This application is made to support the transition to independence of Dr. Aileen Keating, a post-doctoral fellow in the Department of Physiology at the University of Arizona. Dr. Keating will be mentored through the first two years of the award by Dr. Patricia B. Hoyer and will be co-mentored by Dr. Donna Zhang (University of Arizona) and Dr. Jodi Flaws (University of Illinois). Dr. Hoyer's research focuses on the effects of environmental chemicals on small pre-antral ovarian follicles. Specifically, her laboratory has developed a model of environmental xenobiotic exposure in the ovary, using the occupational chemical 4-vinylcyclohexene diepoxide (VCD). VCD selectively destroys small pre-antral follicles in the ovaries of rats and mice. Destruction of the small, pre-antral pool of ovarian follicles can lead to premature ovarian failure (early menopause in women). The research outlined in this application will complement but not overlap with work carried out in Dr. Hoyer's laboratory. With the trend in recent years for women to have children later in life, environmental exposures that reduce the reproductive years are of concern. Additionally, menopause is known to be associated with increased risk for cardiovascular disease, osteoporosis, ovarian cancer and depression. Thus, chemicals that accelerate the onset of menopause are of concern in women. Previous research has investigated a role for ovarian metabolism in mediating the response to ovotoxic chemicals. VCD can be metabolized to an inactive form in the ovary through the action of the Glutathione S-transferase (GST) family of proteins. Additionally, GSTs can also participate in regulating signaling pathways. The specific aims proposed in this application will investigate the role and regulation of GST signaling in the rat ovary in response to VCD exposure. Specific aim 1 will investigate whether GSTpi/mu form protein: protein complexes with pro-apoptotic proteins and to determine if, in response to VCD, these protein: protein complexes dissociate and apoptosis occurs. Specific aim 2 will determine if VCD-induced increased nuclear phosphorylated c-jun alters transcriptional activity of ovarian genes, while specific aim 3 will determine the role of the NRF2 protein in regulation of GSTpi and mu. The findings will demonstrate how GST might simultaneously protect against and enhance VCD-induced ovotoxicity.